Lymphoplasmacytic Lymphoma and Waldenstrom Macroglobulinemia



Lymphoplasmacytic Lymphoma and Waldenstrom Macroglobulinemia


Pei Lin, MD





Key Facts


Terminology



  • LPL is a neoplasm of small B lymphocytes ± plasmacytoid features and plasma cells that does not meet criteria for any other small B-cell lymphoma showing plasmacytic differentiation


  • WM is LPL involving bone marrow associated with an IgM paraprotein of any level


Clinical Issues



  • Symptoms and signs of patients with WM are related to



    • Tissue infiltration by neoplastic cells or


    • Effects of elevated IgM paraprotein


  • WM is usually indolent; median survival: 5-10 years


Microscopic Pathology



  • Bone marrow involvement is constant in WM


  • 3 subtypes of WM are recognized



    • Polymorphous subtype predicts poorer prognosis


Ancillary Tests



  • LPL and WM have 2 immunophenotypic components



    • B cells and plasmacytoid/plasma cells


  • Del6q is the most common cytogenetic aberration in WM, ˜ 40% of cases


  • IgH translocations are uncommon


Top Differential Diagnoses



  • Marginal zone lymphoma


  • Chronic lymphocytic leukemia/small lymphocytic lymphoma with plasmacytic differentiation


  • Plasma cell myeloma, small cell variant


  • Splenic marginal zone lymphoma







Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia (LPL/WM) involving lymph node. Low-power view shows a diffuse pattern of growth with patent sinuses image that contain histiocytes.






LPL/WM involving lymph node. The proliferating cells are small lymphocytes, and a subset of cells has plasmacytoid features.


TERMINOLOGY


Abbreviations



  • Lymphoplasmacytic lymphoma (LPL)


  • Waldenström macroglobulinemia (WM)


Synonyms



  • Terms used in earlier lymphoma classification systems are not exact synonyms as the definition of LPL has been refined over the years


  • Older terms that included LPL along with other B-cell lymphomas include



    • Well-differentiated lymphocytic, plasmacytoid (Rappaport classification)


    • Immunocytoma, lymphoplasmacytic type (Kiel classification)


    • Malignant lymphoma, small lymphocytic, plasmacytoid (Working Formulation)


    • Lymphoplasmacytoid lymphoma (REAL classification)


  • Terms “LPL” and “WM” are often used interchangeably, but the 2 are not identical



    • WM represents great majority of LPL cases


Definitions



  • LPL is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells that does not meet criteria for any other type of small B-cell lymphoma showing plasmacytic differentiation



    • LPL is usually associated with serum monoclonal paraprotein



      • Usually IgM; rarely IgG or IgA


      • Monoclonal paraprotein is not required for diagnosis of LPL


  • WM is LPL involving bone marrow associated with an IgM paraprotein



    • No specific cutoff level of IgM is required


ETIOLOGY/PATHOGENESIS


Infectious Agents



  • Hepatitis C is implicated in some cases of LPL; data are controversial


Genetic Predisposition



  • Familial cases of WM are reported



    • Usually occurs in younger patients


  • Monoclonal gammopathy of unknown significance (MGUS) is most likely a precursor of WM


CLINICAL ISSUES


Epidemiology



  • Incidence



    • ˜ 1% of non-Hodgkin lymphomas


  • Age



    • Median age: 63 to 71 years


  • Gender



    • Male to female ratio = 2:1


  • Ethnicity



    • Whites are more frequently affected than African Americans or Asians


Presentation



  • Relatively little data are available for patients with LPL that do not also have WM


  • About 25% of patients with WM are asymptomatic, so-called smoldering WM


  • Symptoms and signs of patients with WM are related to



    • Tissue infiltration by neoplastic cells or


    • Effects of elevated IgM paraprotein


  • Anemia due to bone marrow infiltration is common and causes fatigue and weakness



    • Bilineage cytopenia or pancytopenia can occur if infiltration by WM is extensive



  • Hepatomegaly occurs in ˜ 20% and splenomegaly in ˜ 15% of WM patients



    • WM can involve gastrointestinal tract, kidney, and other extramedullary sites


  • Lymphadenopathy in ˜ 15% of WM patients



    • Lymphadenopathy is usually mild compared with other types of non-Hodgkin lymphoma


  • Elevated serum IgM paraprotein levels can cause variety of symptoms



    • Hyperviscosity syndrome occurs in 5-15% of cases



      • Headache, vision disturbance (retinopathy), neurologic changes, and cardiac failure


      • Bing-Neel syndrome is central nervous system manifestation


    • Cryoglobulinemia, cold agglutinin hemolysis, autoimmune thrombocytopenia



      • Type II cryoglobulinemia associated with HCV may cause Raynaud phenomenon, arthralgia, skin purpura, and vasculitis


      • IgM-associated neuropathy is autoimmune mediated and tends to be distal, sensory, and symmetric


    • Deposition of IgM in skin and gastrointestinal tract causes related symptoms


  • Rare manifestations include amyloidosis or light-chain deposition disease



    • Any site: Most common in kidney, skin, or bone marrow


Laboratory Tests



  • IgM monoclonal protein is usually present in serum



    • WM



      • IgM paraprotein is required for diagnosis


      • No cutoff level for IgM in serum


    • LPL



      • IgM paraprotein not required for diagnosis


      • Rarely, IgA or IgG paraprotein alone or coexisting with IgM in serum


  • Other laboratory abnormalities well described in WM patients



    • Elevated erythrocyte sedimentation rate, cytopenia (usually anemia)


    • Elevated serum levels of LDH or β-2 microglobulin


Treatment



  • Treatment regimens are best defined for WM patients



    • Alkylating agents (chlorambucil), nucleoside analogs (cladribine or fludarabine), or single-agent rituximab is used


    • Autologous or allogeneic stem cell transplantation in eligible candidates


    • Plasmapheresis for hyperviscosity syndrome, cryoglobulinemia, neuropathy, amyloidosis, and light chain nephropathy


    • Corticosteroids for autoimmune hemolytic anemia or thrombocytopenia


  • No consensus on optimal therapy of LPL patients without WM or serum IgM paraprotein



    • For cases without serum paraprotein: Patients often treated with low-grade B-cell lymphoma regimens


Prognosis



  • WM



    • Usually indolent; median overall survival: 5-10 years


    • International prognostic scoring system designed to stratify patients into low-, intermediate-, and highrisk groups



      • Age > 65 years


      • Hemoglobin ≤ 11.5 g/dL


      • Platelet count ≤ 100 X 109


      • Serum β-2 microglobulin > 3 mg/L


      • Serum M protein concentration > 7 g/dL


      • 5-year survival rates are 87%, 68%,and 36%, respectively, for low-, intermediate- and high-risk groups


    • Poor performance status and elevated serum LDH level also predict poorer prognosis


MACROSCOPIC FEATURES


Size



  • Lymph nodes are usually only modestly enlarged



MICROSCOPIC PATHOLOGY


Histologic Features



  • Lymph node



    • Involvement is usually total or subtotal, extending through capsule into perinodal adipose tissue


    • Pattern of growth is diffuse, but sinuses often are patent


    • Small residual follicles, usually in subcortical areas


    • Lymphoma cells are small ± plasmacytoid differentiation; monocytoid B cells can be seen


    • Blood vessels and sinuses may appear to be markedly dilated


    • Epithelioid histiocytes may be abundant or form scattered clusters


    • Hemosiderin or amyloid deposition


    • Scattered mast cells


  • Bone marrow involvement is constant in WM



    • Pattern of infiltration can be diffuse, interstitial, and nodular


  • 3 subtypes of WM are recognized



    • Lymphoplasmacytoid: Usually composed of monotonous small mature lymphocytes with varying degrees of plasmacytoid differentiation


    • Lymphoplasmacytic: Usually composed of lymphocytes and plasmacytic (Marschalko) cells; ± Dutcher or Russell bodies


    • Polymorphous: Has increased (5-10%) large cells; likely represents initial progression to large B-cell lymphoma


    • Subtypes do not predict level of serum IgM


  • Peripheral blood smear



    • Rouleaux formation is common if IgM paraprotein level is high


    • Leukemic involvement (i.e., high leukocyte count) is unusual


    • Occasional neoplastic cells can be present


  • WM and LPL can be associated with so-called crystalstoring histiocytosis


  • Transformation of WM to diffuse large B-cell lymphoma (DLBCL) occurs in small subset of patients



    • WM and DLBCL components are usually of identical light chain type, suggesting clonal relationship


    • Serum IgM levels may paradoxically decrease


    • EBV is not usually implicated in transformation


  • Rare patients with WM can develop classical Hodgkin lymphoma (CHL)



    • Clonal relationship between WM and CHL is unknown


ANCILLARY TESTS


Immunohistochemistry



  • LPL and WM have 2 components: B cells and plasmacytoid/plasma cells


  • B cells



    • pax-5(+), CD19(+), CD20(+), CD22(+)


    • CD45/LCA(+), Bcl-2(+), cytoplasmic Ig(-)


    • CD5(-), CD10(-), Cyclin-D1(-), Bcl-6(-)


  • Plasmacytoid/plasma cells



    • CD38(+), CD138(+), CD20(-), pax-5(-/+)


    • Monotypic cytoplasmic Ig light chain (+), IgM(+)


    • Monotypic plasma cells may not be demonstrable in lymphoplasmacytoid subtype


  • Ki-67 typically low, p53(-), CD3(-)


Flow Cytometry



  • B cells



    • Surface IgM(+), Ig light chain (+), CD19(+), CD20(+)


    • Usually CD5(-), CD10(-), CD23(-)


    • Subset of cases may express CD5, CD10, or CD23



      • CD5 expression can be distinct or variable


      • CD10(+) cases are usually Bcl-6(-)


      • CD23 expression is usually dim/partial


    • CD11c(+/-), CD22(+/- dim), FMC-7(+/-), CD43(+/-)


    • CD25(-/+), CD103(-)


  • Plasma cells



    • Cytoplasmic IgM(+), Ig light chain (+)


    • CD19(+), CD38(+), CD138(+)


    • IgG type of LPL may not coexpress CD19 and CD138


    • Monotypic plasma cells may be only evidence of persistent disease after chemotherapy


Cytogenetics



  • Cytogenetic data are available for WM



    • Deletion of 6q in 40% of cases


    • Trisomy 4 in 20% of cases


    • Deletion of 13q in subset


    • Trisomy 3 is rare


    • Frequency of these abnormalities has not been confirmed in lymph node


  • IgH translocations are uncommon in WM


  • PAX5-IgH/t(9;14) is neither specific nor common in WM


In Situ Hybridization



  • EBER(-)


Array CGH



  • Deletions of 6q23 and 13q14


  • Gains of 3q13-q28, 6p, and 18q


  • Gains of 4q and 8q occur in 12% and 10% of WM cases, respectively

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lymphoplasmacytic Lymphoma and Waldenstrom Macroglobulinemia

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